1. Field of the Invention
The present invention relates to the use of estramustine phosphate, a non-nitrogen mustard carbamate derivative of estradiol-17b-phosphate, as a high dose infusion. The present invention further relates to methods to potentiate intravenously administered estramustine phosphate and to methods for treating cancer by intravenously administering estramustine phosphate.
2. Discussion of the Background
Cytotoxic effects have been shown to be due to the intact estramustine molecule (Hartley-Asp, 1982). Tissue culture studies have shown that estramustine (EM) is an anti-mitotic agent, causing a dose-dependent blocking of tumor cell division in the metaphase (Hartley-Asp, 1984). Metaphase arrest is known to be caused by an interference of drugs with the microtubule structure that forms the mitotic spindle. It has been shown, with the help of immunohistochemistry, that dose-dependent disturbances of interphase microtubules occur in cultured human prostatic cells (Mareel 1988, Dahllof 1993). Treatment with EM in vitro inhibited the assembly of microtubules composed of only tubulin demonstrating a direct interaction with tubulin (Dahllof 1993). In addition, an interaction with microtubule associated proteins (MAPs) has been demonstrated (Stearns 1988). MAPs are high molecular weight proteins that are believed to be important in stabilizing microtubules. That EM exhibits the mechanism of action of an anti-mitotic agent has been confirmed in vivo (Eklöv, 1992).
Estramustine phosphate is thus an anti-mitotic agent currently used in the treatment of advanced adenocarcinoma of the prostate. As a single agent, its activity in hormone-refractory prostate cancer is comparable to that of several other cytotoxic agents that have been studied in a series of multi-institutional, randomized trials by the National Prostatic Cancer Project (Murphy, 1983). While the drug is usually administered orally at a dose of 10-15 mg/kg/day, it is approved for intravenous administration in several countries. However, estramustine phosphate when administered intravenously has been used at dosages and according to a schedule paralleling the oral administration for the drug, i.e. at recommended dosages of 300-600 mg daily given intravenously and usually repetitively over for several consecutive days. This is then followed by orally administered drug.
In the published material, details from about 500 patients who have been treated with the intravenous formulation initially which was then followed by oral treatment can be found. Induction schedules employing 300-600 mg intravenous daily for 7-21 days, followed by daily oral doses, were typical in these studies. The drug was administered as a slow intravenous injection or as a bolus at 300 mg/day, and thrombophlebitis and local irritation at the peripheral intravenous injection sites were considered major limitations of drug administration requiring the establishment of central line administration in many patients or discontinuation of treatment. At 450 mg/day, Nagel and Kölln (1977) stated that this led to so “severe gastrointestinal problems that 300 mg/day was taken as the maximum intravenous daily dose.” In a compilation, by Andersson et al, of 245 patients recevn 300-600 mg/day for 21 days followed by the same dose once or twice weekly for 2 months, 20% of the patients exhibited thrombophlebitis, 17% exhibited gastrointestinal problems and 9% exhibited liver disturbances. Toxicities resulting from such repetitive dosing schedules often require drug discontinuation (Lundgren, 1995). Maier (1990), administered daily intravenous doses of 900 mg/day for 7-10 days, followed by oral therapy, without reporting phlebitis but severe liver problems did occur in 11 of 18 patients (61%) with one death due to toxic liver failure.
The state of the art thus typically utilized intravenous estramustine phosphate formulations as a single-agent method for initiating a long term oral estramustine therapy. Furthermore, intravenous administration of estramustine phosphate at higher dosages is generally considered prohibitive due to toxicity. It is neither known nor obvious to the art that single dose, high-dosage administration of estramustine phosphate is feasible intravenously. While dosing up to 1200 mg/m2 have been given orally (Keren-Rosenberg, 1997), differences in drug metabolism and bioavailability do not permit extrapolation to the high dose intravenous formulation, with relative bioavailability of estromustine after oral administration found to be only 44%, (Gunnarsson, 1984), with the phosphate moiety dephosphorylated in the oral formulation in contrast to the intravenous formulation. Furthermore, it is not known in the art that intravenous estramustine phosphate can be used in combinational chemotherapy regimens, including the use of higher dose intravenous estramustine phosphate. Furthermore, it is not known to the art that intravenous estramustine phosphate has clinical utility for cancers other than for the prostate cancer indication.
In previous work, Dr. Beryl Hartley-Asp, a co-inventor of this invention, was the first to recognize the synergistic potential of estramustine phosphate with other cytotoxic agents. (Mareel 1988). In several experiments, it was demonstrated that prolonged exposure to estramustine was necessary to achieve potentiation. Consequently, daily dosing was deemed necessary leading to the use of the ORAL preparation as previous data from the intravenous (IV) preparation suggested that achievement of constant high levels would not be clinically achievable with IV dosing.
Additive and possibly synergistic antimicrotubule effects in cells in vitro have been shown for estramustine and many other cytotoxic agents, (Mareel 1988, Speicher 1992, Pienta 1993, Batra,1996). Thus, the combination of estramustine phosphate with other drugs in humans has been carried out using ORAL administration of estramustine phosphate. Phase II trials (Seidman, 1992,.Hudes, 1992, Pienta, 1994, Hudes, 1996) with Estramustine phosphate combined with vinblastine, have been carried out in hormone refractory prostate cancer. In these trials a 50-75% decrease in prostate specific antigen was demonstrated among 88 patients. The most frequent toxicity was mild to moderate nausea. Of particular note is the 10.5% (4/37) incidence of significant cardiovascular toxicity including one deep venous thrombosis (DVT), one myocardial infarction, one episode of congestive heart failure, and one reversible neurologic event which required stopping therapy in these patients and which can be attributed to estramustine phosphate. In another Phase II trial carried out by Pienta et al (1994), estramustine phosphate (oral) was combined with Etoposide. Fifty two patients were evaluable; including 20 patients with soft tissue disease, in which 3 complete responses (CR) (15%) and 6 partial responses (PR) (30%) were observed. In 32 patients with bone metastases 8 patients improved (25%), and 12 patients were stable (38%). Overall 13 men (25%) had a 75% decrease in prostate specific antigen, and 28 men (54%) had a 50% decrease. A Phase I-II study of Taxol (Hudes, 1992) and estramustine phosphate was carried out in seventeen patients with hormone refractory prostate cancer. Six patients had measurable disease and 3 of these obtained a PR of 2+, 6, and 8 months. Prostate specific antigen (PSA) decreased by ≧50% in 58.8%. Median duration of response was 7 months. Grade 3-4 granulocytopenia and mucositis occurred in 2 patients, nausea grade 1-2 (70.5%) and grade 3 in one patient. Edema was seen in 8 patients (47%) and transient hepatic enzyme elevation of grade 1-3 in 6 patients (35.2%).
In a recent study, Petrylak et al., (1997), using escalating doses of docetaxel with estramustine phosphate given orally demonstrated an overall prostate specific antigen response rate of 62%. In patients with bidimensionally measurable disease, 3 (43%) achieved a partial response in lymph nodes, and 1 achieved a minor response in ischial mass. This demonstrates that combination treatment with ORAL estramustine phosphate is efficacious. However, combinations of intravenous estramustine phosphate with these cytotoxic agents are not known to the art. Differences in the metabolism, particularly regarding the phosphate moiety, in the oral versus intravenous estramustine phosphate formulations make combinational therapies with the intravenous formulation non-obvious.
In contrast to other anti-mitotic agents, the effect of estramustine phosphate appears to be dependent on the presence of the estramustine binding protein (EMBP) (Eklöv, 1996). This is found under normal conditions only in the prostate (Forsgren, 1979, Flucher, 1989). However, a similar protein has also been identified in many cancerous tissues, as well as prostate tumors, such as lung, breast glioma, colon, pancreas (Björk, 1991, Bergh 1988, Eklöv 1996, Edgren 1996, Von Schoultz, 1994, Bergenheim, 1993). This protein binds estra- and estro-mustine (EaM and EoM) with very high affinity and is thought to be responsible for the selective retention of EoM in the prostate tumor, where a ratio of 1:6 to 1:11 plasma/tumor has been found in prostate cancer patients treated with estramustine phosphate oral and intravenously, respectively (Norlen 1988,Walz 1988). Recently, we have demonstrated a correlation between the levels of EMBP and the levels of EaM and EoM in human prostate tumors after a single intravenous estramustine phosphate dose to patients before radical prostatectomy, indicating that EMBP could be the cause of drug retention (Walz, 1996).